We explore how T cells differentiate into their different lineages and final effector states, particularly from the standpoint of self-tolerance and autoimmunity. Studies on autoimmunity explore the molecular and genetic failures of tolerance in diabetes, rheumatoid arthritis and in the disease that appears in Aire-deficient individuals. Major questions tackled are why thymic tolerance is defective in these models, what triggers the autoimmune processes, how their progression is regulated. We ask where and how regulatory “Treg” cells are generated and control autoimmune destruction. Molecular investigations tackle how the Aire transcription factor controls the ectopic expression of self-antigens in the thymus, or how FoxP3 coordinates with other elements in specifying the different facets of the Treg phenotype. Our research involves many collaborations across the campus, and a wide range of technologies are applied to these questions (manipulation of the mouse germline, gene expression profiling, mass spectrometry, RNAi screens). Imaging tools are used to analyze and track autoimmune inflammation in vivo, in mice and human patients. The lab also has an interest in bioinformatic approaches to explore the regulation and connectivity of gene expression at the “Systems Immunology” level. Most of our work involves mouse models, but we also translate some of the leads to human diseases.
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Papers & Publications:
Nishio J, Gaglia, J, Turvey, S, Benoist C, and Mathis, D. Islet recovery and reversal of murine type-1 diabetes, in the absence of infused spleen cell contribution. Science (2006), 311,1775-8.
Binstadt B, Pate P, Alencar H, Nigrovic P, Lee DM, Mahmood U, Weissleder R, Mathis D, and Benoist C. Particularities of the vasculature can promote the organ specificity of autoimmune attack. Nature Immunol. (2006), 7,284-92.
Hyatt G, Melamed R, Park R, Seguritan R, Laplace C, Poirot L, Zucchelli S, Obst R, Matos M, Venanzi E, Goldrath A, Nguyen L, Luckey J, Yamagata T, Herman A, Jacobs J, Mathis D, and Benoist C. Gene expression microarrays: glimpses at the immunological genome. Nat. Immunol. (2006), 7, 686-91.
S. Zucchelli, P. Holler, T. Yamagata, M. Roy, C. Benoist, D. Mathis: Defective central tolerance induction in NOD mice: genomics and genetics. Immunity (2005), 22, 385-96.
T. Yamagata, D. Mathis, C. Benoist: Self-reactivity in thymic double-positive cells commits cells to a CD8 alpha alpha lineage with characteristics of innate immune cells. Nat Immunol (2004), 5, 597-605. |
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